title: Lipid-rich enteral nutrition regulates mucosal mast cell activation via the vagal anti-inflammatory reflex.
abstract: Nutritional stimulation of the cholecystokinin-1 receptor (CCK-1R) and nicotinic acetylcholine receptor (nAChR)-mediated vagal reflex was shown to reduce inflammation and preserve intestinal integrity. Mast cells are important early effectors of the innate immune response; therefore modulation of mucosal mast cells is a potential therapeutic target to control the acute inflammatory response in the intestine. The present study investigates intestinal mast cell responsiveness upon nutritional activation of the vagal anti-inflammatory reflex during acute inflammation. Mucosal mast cell degranulation was induced in C57/Bl6 mice by administration of Salmonella enterica LPS. Lipid-rich enteral feeding prior to LPS significantly decreased circulatory levels of mouse mast cell protease at 30 min post-LPS compared with isocaloric low-lipid nutrition or fasting. CCK-1R blockage reversed the inhibitory effects of lipid-rich feeding, whereas stimulation of the peripheral CCK-1R mimicked nutritional mast cell inhibition. The effects of lipid-rich nutrition were negated by nAChR blockers chlorisondamine and α-bungarotoxin and vagal intestinal denervation. Accordingly, release of β-hexosaminidase by MC/9 mast cells following LPS or IgE-ovalbumin complexes was dose dependently inhibited by acetylcholine and nicotine. Application of GSK1345038A, a specific agonist of the nAChR α7, in bone marrow-derived mast cells from nAChR β2-/- and wild types indicated that cholinergic inhibition of mast cells is mediated by the nAChR α7 and is independent of the nAChR β2. Together, the present study reveals mucosal mast cells as a previously unknown target of the nutritional anti-inflammatory vagal reflex.
authors.affiliation: Dept. of Surgery at Maastricht Univ. Medical Centre+, Universiteitssingel 50, 6229 ER Maastricht, the Netherlands. w.buurman@maastrichtuniversity.nl.
authors.forename: Jacco J
authors.initials: JJ
authors.lastname: de Haan
authors.forename: M'hamed
authors.initials: M
authors.lastname: Hadfoune
authors.forename: Tim
authors.initials: T
authors.lastname: Lubbers
authors.forename: Caroline
authors.initials: C
authors.lastname: Hodin
authors.forename: Kaatje
authors.initials: K
authors.lastname: Lenaerts
authors.forename: Akihiko
authors.initials: A
authors.lastname: Ito
authors.forename: Isabelle
authors.initials: I
authors.lastname: Verbaeys
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Skynner
authors.forename: Cathy
authors.initials: C
authors.lastname: Cailotto
authors.forename: Jan
authors.initials: J
authors.lastname: van der Vliet
authors.forename: Wouter J
authors.initials: WJ
authors.lastname: de Jonge
authors.forename: Jan-Willem M
authors.initials: JW
authors.lastname: Greve
authors.forename: Wim A
authors.initials: WA
authors.lastname: Buurman
mesh_terms: D000818:Animals; D015550:Cell Degranulation / Q000187:drug effects; D002460:Cell Line; D018679:Cholinergic Agonists / Q000494:pharmacology; D053818:Chymases / Q000097:blood; D004041:Dietary Fats / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004750:Enteral Nutrition; D006633:Histamine Antagonists / Q000494:pharmacology; D018928:Immunity, Mucosal; D007249:Inflammation / Q000097:blood / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology* / Q000294:innervation* / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018733:Nicotinic Antagonists / Q000494:pharmacology; D043886:Receptor, Cholecystokinin A / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D012018:Reflex; D014629:Vagotomy, Proximal Gastric; D014630:Vagus Nerve / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology* / Q000601:surgery; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
chemical_list: D018679:Cholinergic Agonists; D053818:Chymases; D004041:Dietary Fats; D006633:Histamine Antagonists; D008070:Lipopolysaccharides; D018733:Nicotinic Antagonists; D043886:Receptor, Cholecystokinin A; D011978:Receptors, Nicotinic; D001619:beta-N-Acetylhexosaminidases
keywords: cholecystokinin; cholinergic anti-inflammatory pathway; enteral nutrition; nicotinic acetylcholine receptor; vagus nerve